Retromer is involved in epithelial Na⁺ channel trafficking

Abstract

The epithelial sodium channel, ENaC, located at the apical membrane in many epithelia, is the rate-limiting step for sodium reabsorption. Tight regulation of the plasma membrane population of ENaC is required as hyper- or hypotension may result if too many or too few ENaCs are present. Endocytosed ENaC travels to the early endosome and is then either trafficked to the lysosome for degradation or recycled back to the plasma membrane. Recently, the retromer recycling complex, located at the early endosome, has been implicated in plasma membrane protein recycling pathways. We hypothesized that retromer is required for recycling of ENaC. Stabilization of retromer function with the retromer stabilizing chaperone R55 increased ENaC current, while knockdown or overexpression of individual retromer and associated proteins altered ENaC current and cell surface population of ENaC. KIBRA was identified as an ENaC binding protein allowing ENaC to link to Snx4 to alter ENaC trafficking. Knockdown of the retromer-associated cargo-binding Snx27 protein did not alter ENaC current, whereas CCDC22, a CCC-complex protein, coimmunoprecipitated with ENaC and CCDC22 knockdown decreased ENaC current and population at the cell surface. Together our results confirm that retromer and the CCC complex play a role in recycling of ENaC to the plasma membrane.

Sorting nexins: role in the regulation of blood pressure

“…For example, SNX4 is required for the trafficking of the epithelial sodium channel (ENaC), which is involved in sodium reabsorption in the late distal convoluted tubule, connecting tubule, and collecting duct of the kidney [117][118][119][120]. SNX4-mediated trafficking of ENaC may involve the kidney and brain protein, KIBRA [121]. Depletion of Snx27, a retromer-associated protein, does not alter ENaC activity [121].…”

“…SNX4‐mediated trafficking of ENaC may involve the kidney and brain protein, KIBRA [121]. Depletion of Snx27 , a retromer‐associated protein, does not alter ENaC activity [121]. However, SNX27 can directly interact with the C‐terminus of NHE3 to regulate its trafficking to the renal brush border membrane [42].…”

Pharmacologic enhancement of retromer rescues endosomal pathology induced by defects in the Alzheimer’s gene SORL1

“…Enhancing endosomal trafficking via targeting the retromer complex, which is intimately associated with SORL1 , may be a feasible therapeutic strategy. Small molecule pharmacologic chaperones that stabilize the cargo recognition core of retromer increase expression of retromer subunits ( Cheung et al., 2020 ; Fjorback et al., 2012 ; Hirayama et al., 2019 ; Mecozzi et al., 2014 ; Young et al., 2018 ). In neuronal culture, these molecules reduce amyloidogenic processing of APP and increase the flow of SORLA through endosomes ( Mecozzi et al., 2014 ).…”